WO2007096647A2 - Composé - Google Patents

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Publication number
WO2007096647A2
WO2007096647A2 PCT/GB2007/000655 GB2007000655W WO2007096647A2 WO 2007096647 A2 WO2007096647 A2 WO 2007096647A2 GB 2007000655 W GB2007000655 W GB 2007000655W WO 2007096647 A2 WO2007096647 A2 WO 2007096647A2
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Prior art keywords
group
alkyl
substituted
optionally substituted
ring
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PCT/GB2007/000655
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English (en)
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WO2007096647A3 (fr
Inventor
Nigel Vicker
Gillian Margaret Allan
Harshani Rithma Ruchiranani Lawrence
Joanna Mary Day
Atul Purohit
Michael John Reed
Barry Victor Lloyd Potter
Original Assignee
Sterix Limited
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Priority claimed from GB0603894A external-priority patent/GB0603894D0/en
Priority claimed from GB0615464A external-priority patent/GB0615464D0/en
Application filed by Sterix Limited filed Critical Sterix Limited
Priority to CA002643670A priority Critical patent/CA2643670A1/fr
Priority to EP07712778A priority patent/EP2013176A2/fr
Publication of WO2007096647A2 publication Critical patent/WO2007096647A2/fr
Publication of WO2007096647A3 publication Critical patent/WO2007096647A3/fr
Priority to US12/199,364 priority patent/US20090186900A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/22—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/74—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of a saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/72—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms
    • C07C235/76—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C235/78—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of an unsaturated carbon skeleton the carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/70—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/84—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups and doubly-bound oxygen atoms bound to the same carbon skeleton with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
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    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/62—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
    • C07C45/46—Friedel-Crafts reactions
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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    • C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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    • C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
    • C07C45/68—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C07C45/70—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form
    • C07C45/71—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms by reaction with functional groups containing oxygen only in singly bound form being hydroxy groups
    • C—CHEMISTRY; METALLURGY
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/703—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups
    • C07C49/747—Unsaturated compounds containing a keto groups being part of a ring containing hydroxy groups containing six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/753—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups
    • C07C49/755—Unsaturated compounds containing a keto groups being part of a ring containing ether groups, groups, groups, or groups a keto group being part of a condensed ring system with two or three rings, at least one ring being a six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C49/587—Unsaturated compounds containing a keto groups being part of a ring
    • C07C49/757—Unsaturated compounds containing a keto groups being part of a ring containing —CHO groups
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/82—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups
    • C07C49/83—Ketones containing a keto group bound to a six-membered aromatic ring containing hydroxy groups polycyclic
    • C—CHEMISTRY; METALLURGY
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/84—Ketones containing a keto group bound to a six-membered aromatic ring containing ether groups, groups, groups, or groups
    • C—CHEMISTRY; METALLURGY
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    • C07C49/00—Ketones; Ketenes; Dimeric ketenes; Ketonic chelates
    • C07C49/76—Ketones containing a keto group bound to a six-membered aromatic ring
    • C07C49/86—Ketones containing a keto group bound to a six-membered aromatic ring containing —CHO groups
    • C—CHEMISTRY; METALLURGY
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C59/40—Unsaturated compounds
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    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/67—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of saturated acids
    • C07C69/708—Ethers
    • C07C69/712—Ethers the hydroxy group of the ester being etherified with a hydroxy compound having the hydroxy group bound to a carbon atom of a six-membered aromatic ring
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    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
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    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/40—Acylated substituent nitrogen atom
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
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    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
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    • C07C2602/04—One of the condensed rings being a six-membered aromatic ring
    • C07C2602/10—One of the condensed rings being a six-membered aromatic ring the other ring being six-membered, e.g. tetraline

Definitions

  • the present invention relates to a compound.
  • the present invention provides compounds capable of inhibiting 17 ⁇ -hydroxysteroid dehydrogenase (17 ⁇ - HSD).
  • the aim in the treatment is no longer to cure but to reach a palliative control. This is the case when metastases of the tumour have reached locations such as bones, skin, lymph, node or brain.
  • the treatment varies depending on the hormonal status of the patient (whether it is a pre- or post-menopausal woman to be treated) and depending on the type of tumour. Certain tumours have indeed been proven to rely on estrogens for their growth and development, leading to what is called a Hormone Dependent Breast Cancer (HDBC, see 1-1). While non HDBC are treated with chemotherapy, where the aim is to kill differentially tumour cells using a combination of cytotoxic agents, 5 HDBC are expected to respond to endocrine therapy.
  • HDBC Hormone Dependent Breast Cancer
  • hER human Oestrogen Receptor
  • ER+ oestrogen-receptor- positive
  • ER- oestrogen-receptor-negative
  • Anti-oestrogens as antagonists of the oestrogen receptor, have been one of the first treatment considered for HDBC. Their action rely on their ability to bind competitively to the specific receptor protein hER, thus preventing access of endogenous estrogens to their specific binding site. Consequently, the natural hormone is unable to maintain tumour growth.
  • tamoxifen (below) is the most widely used because of the very low toxicity profile of the molecule. Despite its non-steroidal skeleton, tamoxifen possesses a mixed agonist-antagonist activity that limits its therapeutic potential. 9 In addition, some form of drug resistance has been reported in patients after long-term tamoxifen treatment. 10
  • Novel pure anti-oestrogenic drugs such as ICI 164384 (below) have since been discovered but the loss of potency compared with that of tamoxifen suggested the need to design more highly potent targets. 11
  • the use of therapeutic agents that inhibit one or several enzyme of the steroid biosynthesis pathway represents another important strategy to control of the development of oestrogen-dependent tumours.
  • the enzyme aromatase which converts androgenic C19 steroids to estrogenic C18 steroids, has been the prime target for reducing oestrogen levels.
  • This enzyme complex which contains a cytochrome P450 haemoprotein, catalyses the aromatisation of the androgen A-ring with the subsequent loss of the C19 methyl group to yield estrogens.
  • Aminoglutethimide (below) was the first aromatase inhibitor used for the treatment of breast cancer. It however showed a number of undesirable side effects given its wide spectrum of inhibitory effects on other P450-dependant enzymes, and attempts to improve on the original structure have led to a number of non-steroidal compounds entering clinical trials. 15 The last generation developed compounds such as letrozole, which combine high potency and high selectivity for the enzyme, and are also better tolerated.
  • Generation I aminoglutethimide, AG; generation III, letrozole.
  • aromatase inhibitors are reserved as second line treatment for advanced HDBC patients whose diseases are no longer controlled by tamoxifen.
  • tamoxifen because of the extreme good toxicity profile of some of the latest aromatase inhibitors, recent clinical trials have been conducted to assess their suitability as first line treatment for HDBC.
  • estrogens are synthesised from the highly available precursor oestrone-sulphate, via two enzymes (scheme below): steroid sulphatase (STS) which hydrolyses oestrone-sulphate into oestrone, and 17 ⁇ -hydroxysteroid dehydrogenase (17 ⁇ -HSD) which reduces oestrone into oestradiol.
  • STS steroid sulphatase
  • 17 ⁇ -HSD 17 ⁇ -hydroxysteroid dehydrogenase
  • AR aromatase
  • ST steroid sulfotransferase
  • STS steroid sulphatase
  • 17 ⁇ -HSD 17 ⁇ -hydroxysteroid dehydrogenase
  • 3 ⁇ -IS 3 ⁇ -hydroxysteroid dehydrogenase ⁇ 5 , ⁇ 4 -isomerase
  • ER oestrogen receptor
  • EMATE was shown to inhibit steroid sulphatase activity in a time- and concentration-dependent manner 17 and was active in vivo on oral administration. 18 It was however revealed to be highly estrogenic which raised the need to design STS inhibitors devoid of agonist activity on hER.
  • PCT/GB92/01587 teaches novel steroid sulphatase inhibitors and pharmaceutical compositions containing them for use in the treatment of oestrone dependent tumours, especially breast cancer.
  • These steroid sulphatase inhibitors are sulphamate esters, such as N,N-dimethyl oestrone-3-sulphamate and, preferably, oestrone-3-sulphamate (EMATE). It is known that EMATE is a potent E1-STS inhibitor as it displays more than 99% inhibition of E1-STS activity in intact MCF-7 cells at 0.1 mM.
  • EMATE also inhibits the E1-STS enzyme in a time- and concentration-dependent manner, indicating that it acts as an active site-directed inactivator.
  • EMATE was originally designed for the inhibition of E1-STS, it also inhibits dehydroepiandrosterone sulphatase (DHA-STS), which is an enzyme that is believed to have a pivotal role in regulating the biosynthesis of the oestrogenic steroid androstenediol.
  • DHA-STS dehydroepiandrosterone sulphatase
  • androstenediol may be of even greater importance as a promoter of breast tumour growth.
  • EMATE is also active in vivo as almost complete inhibition of rat liver E1-STS (99%) and DHA-STS (99%) activities resulted when it is administered either orally or subcutaneously.
  • EMATE has been shown to have a memory enhancing effect in rats.
  • Studies in mice have suggested an association between DHA-STS activity and the regulation of part of the immune response. It is thought that this may also occur in humans.
  • the bridging O-atom of the sulphamate moiety in EMATE is important for inhibitory activity.
  • these analogues are weaker non-time-dependent inactivators.
  • 17 ⁇ -HSD belongs to a family of isoenzymes, 13 of which have been so far identified and cloned. 27 Each type has a selective substrate affinity and directional activity which means that selectivity of drug action has to be achieved. 17 ⁇ -HSD type 1 is the isotype that catalyses the interconversion of oestrone and oestradiol.
  • 17 ⁇ -HSD inhibitors Unlike STS inhibitors, only few 17 ⁇ -HSD inhibitors have been reported. Most of the steroidal inhibitors for 17 ⁇ -HSD type 1 have in common a D-ring modified structure. Oestradiol derivatives which contain a side-chain with a good leaving group at the 16 ⁇ - position have been shown to be a potent class of inhibitors. In particular, 16 ⁇ - (bromoalkyl)-estradiol 28 where the side-chains exhibit high reactivity towards nucleophilic amino-acids residues in the active site of the enzyme were found to be promising irreversible inhibitors.
  • Analogues containing short bromoalkyl moieties at position 16 exhibited the highest activity with 16 ⁇ -(Bromopropyl)-oestradiol, followed by 16 ⁇ - (Bromobutyl)-oestradiol, the most potent of the series (3 and 4). They, however, turned out to be pure agonists of the oestrogen receptor.
  • 17 ⁇ -HSD type 1 inhibitors 16 ⁇ -(bromopropyl)-oestradiol, 3; 16 ⁇ -(bromopropyl)-oestradiol, 4 and a flavone derivative, apigenin.
  • 16 ⁇ - (broadly)-oestradiol derivatives bearing the C7 ⁇ -alkylamide side chain of the known anti- oestrogen ICI 164384 were synthesised. 29
  • rather poor inhibition of 17 ⁇ -HSD type 1 was obtained, with estrogenic and anti-oestrogenic properties not completely abolished or introduced respectively.
  • Flavonoids which are structurally similar to estrogens, are able to bind to the oestrogen receptor with estrogenic or anti-estrogenic activities. 30 Their action on aromatase activity is well documented and in recent studies, they were found to reduce the conversion of oestrone into oestradiol catalysed by 17 ⁇ -HSD type 1. 31 Flavone derivatives, such as apigenin emerged from a SAR study as a promising compounds with some inhibitory activity on 17 ⁇ -HSD type 1 without being estrogenic at the inhibitory concentration. 32
  • DH Steroid dehydrogenases
  • E2HSD oestradiol 17 ⁇ -hydroxysteroid dehydrogenases
  • E2HSD Type I reduces oestrone (E1) to the biologically active oestrogen, oestradiol (E2), while E2HSD Type Il inactivates E2 by catalysing its oxidation to El
  • the present invention provides novel compounds which are capable of acting as effective 17 ⁇ -hydroxysteroid dehydrogenase (17 ⁇ -HSD) inhibitors.
  • the present invention identifies that the compounds of the present application are effective 17 ⁇ - hydroxysteroid dehydrogenase (17 ⁇ -HSD) inhibitors.
  • Figure 1 shows some of the enzymes involved in the in situ synthesis of oestrone from oestrone sulphate, and oestradiol.
  • STS denotes Steroid Sulphatase
  • E2DH Type I denotes Oestradiol 17 ⁇ -hydroxysteroid dehydrogenase Type I or Oestradiol 17 ⁇ -hydroxysteroid dehydrogenase Type 1 , 3, 5 and/or 7
  • E2DH Type II denotes Oestradiol 17 ⁇ -hydroxysteroid dehydrogenase Type Il or Oestradiol 17 ⁇ -hydroxysteroid dehydrogenase Type 2 and/or 8.
  • the present invention therefore seeks to overcome one or more of the problems associated with the prior art methods of treating breast and endometrial cancers.
  • the present invention provides a use of a compound for the preparation of a medicament that can or affect, such as substantially inhibit, the steroid dehydrogenase pathway - which pathway converts oestrone to and from oestradiol.
  • This aspect of the present invention is advantageous because by the administration of one type of compound it is possible to block the synthesis of oestradiol from oestrone.
  • the present invention provides compounds that have considerable therapeutic advantages, particularly for treating breast and endometrial cancers.
  • the compounds of the present invention may comprise other substituents. These other substituents may, for example, further increase the activity of the compounds of the present invention and/or increase stability (ex vivo and/or in vivo).
  • the present invention provides a compound of Formula I
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted wherein X is a bond or a linker group wherein
  • R 9 is selected from alkyl and halogen groups; and (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NR 1 R 2 ; wherein R 1 and
  • alkenylaryl group wherein the aryl group is substituted (v) alkylheteroaryl group, wherein when heteroaryl group comprises only C and N in the ring, the aryl group is substituted by other than a methyl group
  • R 3 , R 4 , R 5 , R 6 , R 7 , Rg, and Ri 0 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted and/or optionally contains one or more hetero atoms (such as N) wherein X is a bond or a linker group wherein (A) (i) R 9 is selected from alkyl and halogen groups; or (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NR 1 R 2 ; wherein Ri and R 2 are independently selected from H and hydrocarbyl; or (iii) ring A contains one or more hetero atoms or
  • alkylaryl group wherein the aryl group is substituted by other than a C1-10 group
  • alkenylaryl group wherein the aryl group is substituted
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • R 3 , R 4 , R 5 , R 6 and R 7 is selected from alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, and heteroaryl groups or
  • a compound according to the present invention for use in medicine.
  • a pharmaceutical composition comprising a compound of Formula I
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and Ri 0 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted and/or optionally contains one or more hetero atoms (such as N) wherein X is a bond or a linker group wherein
  • R 9 is selected from alkyl and halogen groups; or (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NRiR 2 ; wherein Ri and R 2 are independently selected from H and hydrocarbyl; or (iii) ring A contains one or more hetero atoms or
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group, (xi) -CHO, or together with another of R 3 , R 4 , R 5 , R 6 and R 7 the enol tautomer thereof wherein Rn and Ri 2 are independently selected from H and hydrocarbyl; or
  • R 3 , R 4 , R 5 , R 6 and R 7 is selected from alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, and heteroaryl groups or
  • the present invention provides use of a compound in the manufacture of a medicament for use in the therapy of a condition or disease associated with 17 ⁇ - hydroxysteroid dehydrogenase (17 ⁇ -HSD), wherein the compound is of Formula I
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 are independently selected from -H 1 -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted and/or optionally contains one or more hetero atoms (such as N) wherein X is a bond or a linker group wherein
  • alkenylaryl group wherein the aryl group is substituted
  • alkylheteroaryl group wherein when heteroaryl group comprises only C and N in the ring, the aryl group is substituted by other than a methyl group
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • a compound according to the present invention in the manufacture of a medicament for use in the therapy of a condition or disease associated with steroid dehydrogenase.
  • R 3 , R 4 , R 5 , R 6 , R7, Rg, and R 10 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted and/or optionally contains one or more hetero atoms (such as N) wherein X is a bond or a linker group wherein
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • a compound according to the present invention in the manufacture of a medicament for use in the therapy of a condition or disease associated with adverse steroid dehydrogenase levels.
  • One key advantage of the present invention is that the compounds of the present invention can act as 17 ⁇ -HSD inhibitors.
  • Another advantage of the compounds of the present invention is that they may be potent in vivo.
  • non-oestrogenic compounds means exhibiting no or substantially no oestrogenic activity.
  • Another advantage is that some of the compounds may not be capable of being metabolised to compounds which display or induce hormonal activity.
  • Some of the compounds of the present invention are also advantageous in that they may be orally active.
  • Some of the compounds of the present invention may useful for the treatment of cancer, such as breast cancer, as well as (or in the alternative) non-malignant conditions, such as the prevention of auto-immune diseases, particularly when pharmaceuticals may need to be administered from an early age.
  • cancer such as breast cancer
  • non-malignant conditions such as the prevention of auto-immune diseases, particularly when pharmaceuticals may need to be administered from an early age.
  • some of the compounds of the present invention are also believed to have therapeutic uses other than for the treatment of endocrine-dependent cancers, such as the treatment of autoimmune diseases.
  • the compound is of Formula I
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted and/or optionally contains one or more hetero atoms (such as N) wherein X is a bond or a linker group wherein
  • Rg is selected from alkyl and halogen groups; or (ii) Ri 0 is selected from -OH, oxyhydrocarbyl and -OSO 2 NRiR 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl; or (iii) ring A contains one or more hetero atoms or
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group, (xi) -CHO, or together with another of R 3 , R 4 , R5, Re and R 7 the enol tautomer thereof wherein Rn and R 12 are independently selected from H and hydrocarbyl; or
  • R 3 , R 4 , R 5 , R 6 and R 7 is selected from alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, and heteroaryl groups or
  • R 9 is selected from alkyl and halogen groups; and (ii) Ri 0 is selected from -OH, oxyhydrocarbyl and -OSO 2 NR 1 R 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl.
  • R 9 is selected from alkyl and halogen groups; and (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NRiR 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl, wherein when R 9 is a halogen group and R 10 is -OH, at least one of R 3 , R 4 , Rs, Re and R 7 are as defined in (B), (C), (D) or (E);
  • the compound is of Formula I
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted wherein X is a bond or a linker group wherein (A) (i) R 9 is selected from alkyl and halogen groups; and
  • R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NRiR 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl, wherein when R 9 is a halogen group and Ri 0 is -OH, at least one of R 3 , R 4 , R 5 , Re and R 7 are as defined in (B), (C), (D) or (E); or
  • alkenylaryl group wherein the aryl group is substituted (v) alkylheteroaryl group, wherein when heteroaryl group comprises only C and N in the ring, the aryl group is substituted by other than a methyl group
  • the compound is of Formula Il
  • the compound is of Formula ill
  • the compound is of Formula IV
  • the compound is of Formula V
  • the compound is of Formula Vl
  • halogen is preferably F.
  • the compound is of Formula VII
  • the compound is of Formula VIII
  • At least one of R 3 , R 4 , Rs, Re and R 7 is selected from alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, and heteroaryl groups.
  • R 9 is selected from or R 9 of (A) is selected from ethyl and fluoro groups.
  • R 10 is selected from or Ri 0 of (A) is selected from is selected from -OH and methoxy.
  • the compound of or for use in the present invention comprises ring A.
  • the ring may contain any suitable atoms.
  • ring A may contain C and optionally one or more hetero atoms. Typical hetero atoms include O, N and S 1 in particular N.
  • ring A contains C and optionally one or more N atoms.
  • ring A contains only C atoms i.e. it is carbocyclic.
  • ring A is optionally further substituted.
  • ring A is substituted only by groups R 9 and Ri 0 . It will be understood that the remaining valencies of the atoms of the ring are occupied by H.
  • ring A will contain from 4 to 10 members.
  • ring A will contain 5, 6 or 7 members.
  • ring A contains a nitrogen.
  • group X is a bond or a linker group. In one aspect X is a bond. In one aspect X is a linker group.
  • Formula I may be denoted as follows:
  • the linker group may be any suitable linker group.
  • R 23 is an alkyl group.
  • the R 23 alkyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • the R 23 alkyl group may be branched or straight chain. Preferably the alkyl group is straight chained.
  • R 23 is selected from H and alkyl groups having from 1 to 20 carbons, preferably selected from H and alkyl groups having from 1 to 10 carbons, preferably selected from H and alkyl groups having from 1 to 5 carbons, preferably selected from H and alkyl groups having from 1 , 2 or 3 carbons, most preferably H or methyl.
  • X is selected from CH 2 , O, S and a bond.
  • X is selected from O, S and a bond.
  • the compound of or for use in the present invention comprises ring B.
  • the ring may contain any suitable atoms.
  • ring B may contain C and optionally one or more hetero atoms. Typical hetero atoms include O, N and S, in particular N.
  • ring A contains C and optionally one or more N atoms.
  • ring B contains only C atoms i.e. it is carbocyclic.
  • ring B will contain from 4 to 10 members.
  • ring B will contain 5, 6 or 7 members.
  • R3, R 4 , R5, R 6 , R 7 , Rg, and Ri 0 are independently selected from -H, - OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens.
  • hydrocarbyl group means a group comprising at least C and H and may optionally comprise one or more other suitable substituents.
  • a combination of substituents may form a cyclic group.
  • the hydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group.
  • the hydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur, nitrogen and oxygen.
  • a non-limiting example of a hydrocarbyl group is an acyl group.
  • a typical hydrocarbyl group is a hydrocarbon group.
  • hydrocarbon means any one of an alkyl group, an alkenyl group, an alkynyl group, which groups may be linear, branched or cyclic, or an aryl group.
  • the term hydrocarbon also includes those groups but wherein they have been optionally substituted. If the hydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
  • the hydrocarbyl group is selected from optionally substituted alkyl group, optionally substituted haloalkyl group, aryl group, alkylaryl group, alkylarylakyl group, and an alkene group.
  • the hydrocarbyl group is an optionally substituted alkyl group.
  • the hydrocarbyl group is selected from C 1 -C 10 alkyl group, such as C 1 -C 6 alkyl group, and C 1 -C 3 alkyl group.
  • Typical alkyl groups include C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 7 alkyl, and C 8 alkyl.
  • the hydrocarbyl group is selected from C 1 -Ci 0 haloalkyl group, C 1 -C 6 haloalkyl group, C 1 -C 3 haloalkyl group, C 1 -C 10 bromoalkyl group, C 1 -C 6 bromoalkyl group, and C 1 -C 3 bromoalkyl group.
  • Typical haloalkyl groups include C 1 haloalkyl, C 2 haloalkyl, C 3 haloalkyl, C 4 haloalkyl, C 5 haloalkyl, C 7 haloalkyl, C 8 haloalkyl, C 1 bromoalkyl, C 2 bromoalkyl, C 3 bromoalkyl, C 4 bromoalkyl, C 5 bromoalkyl, C 7 bromoalkyl, and C 8 bromoalkyl.
  • the hydrocarbyl group is selected from aryl groups, alkylaryl groups, alkylarylakyl groups, -(CH 2 )i.i 0 -aryl, -(CHa) 1-I0 -Ph 1 (CHa) 1-I0 -Ph- C 1-10 alkyl, -(CH 2 ) ⁇ -Ph 1 (CH 2 ) L5 -Ph-C L5 alkyl, -(CH 2 ) ⁇ -Ph 1 (CH 2 J 1-3 -Ph-C 1-3 alkyl, -CH 2 - Ph, and -CH 2 -Ph-C(CH 3 ) 3 .
  • the aryl group or one or more of the aryl groups may contain a hetero atom.
  • the aryl group or one or more of the aryl groups may be carbocyclic or more may heterocyclic.
  • Typical hetero atoms include O, N and S, in particular N.
  • the hydrocarbyl group is selected from ⁇ (CH 2 )i. i ⁇ -cycloalkyl, -(CH 2 )i-iQ-C 3-1o cycloalkyl, -(CH 2 ) 1-7 -C 3-7 cycloalkyl, -(CH 2 )i-5-C 3 . 5 cycloalkyl, - (CH 2 )i -3 -C 3-5 cycloalkyl, and -CH 2 - C 3 cycloalkyl.
  • the hydrocarbyl group is an alkene group.
  • Typical alkene groups include C 1 -C 10 alkene group, CrC 6 alkene group, d-C 3 alkene group, such as Ci, C 2 , C 3 , C 4 , C 5 , C 6 , or C 7 alkene group.
  • oxyhydrocarbyl group as used herein means a group comprising at least C, H and O and may optionally comprise one or more other suitable substituents. Examples of such substituents may include halo-, alkoxy-, nitro-, an alkyl group, a cyclic group etc. In addition to the possibility of the substituents being a cyclic group, a combination of substituents may form a cyclic group. If the oxyhydrocarbyl group comprises more than one C then those carbons need not necessarily be linked to each other. For example, at least two of the carbons may be linked via a suitable element or group. Thus, the oxyhydrocarbyl group may contain hetero atoms. Suitable hetero atoms will be apparent to those skilled in the art and include, for instance, sulphur and nitrogen.
  • the oxyhydrocarbyl group is a oxyhydrocarbon group.
  • oxyhydrocarbon means any one of an alkoxy group, an oxyalkenyl group, an oxyalkynyl group, which groups may be linear, branched or cyclic, or an oxyaryl group.
  • the term oxyhydrocarbon also includes those groups but wherein they have been optionally substituted. If the oxyhydrocarbon is a branched structure having substituent(s) thereon, then the substitution may be on either the hydrocarbon backbone or on the branch; alternatively the substitutions may be on the hydrocarbon backbone and on the branch.
  • the oxyhydrocarbyl group is an alkoxy group.
  • the oxyhydrocarbyl group is of the formula Ci -6 O (such as a Ci -3 O).
  • the oxyhydrocarbyl group is and in particular the A ring of the ring system is substituted with, an alkoxy group.
  • the alkoxy group is methoxy
  • halogens refer to F, Cl 1 Br and I.
  • each halogen or at least one halogen is F.
  • each halogen or at least one halogen is Cl.
  • each halogen or at least one halogen is Br.
  • each halogen or at least one halogen is I.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and Ri O is -OH.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and Ri O is a hydrocarbyl group.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 is a oxyhydrocarbyl groups.
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 is cyano (-CN).
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and Ri 0 is nitro (-NO 2 ).
  • At least one of R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and Ri O is a halogen.
  • R 9 is selected from alkyl and halogen groups; or (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NR 1 R 2 ; wherein R-, and R 2 are independently selected from H and hydrocarbyl; or (iii) ring A contains one or more hetero atoms
  • R 9 is selected from alkyl and halogen groups; and (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NRiR 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl.
  • R 9 is selected from alkyl and halogen groups; and (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NR 1 R 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl, wherein when R 9 is a halogen group and Ri 0 is -OH, at least one of R 3 , R 4 , R 5 , R 6 and R 7 are as defined in (B), (C), (D) or (E);
  • R 9 is alkyl and Rio is -OH.
  • R 9 is alkyl and Ri 0 is oxyhydrocarbyl.
  • R 9 is alkyl and R-io is -OSO 2 NR 1 R 2 .
  • R 9 is a halogen and Ri 0 is -OH.
  • R 9 is a halogen and R 10 is oxyhydrocarbyl/
  • R 9 is a halogen and R 10 is -OSO 2 NR 1 R 2 .
  • R 9 is alkyl and Ri 0 is -OH or (b) R 9 is alkyl and R 10 is oxyhydrocarbyl or (c) R 9 is alkyl and R 1 0 is -OSO 2 NR 1 R 2 or (d) R 9 is a halogen and R 10 is oxyhydrocarbyl or (e) R 9 is a halogen and R 10 is -OSO 2 NR 1 R 2 .
  • alkenylaryl group wherein the aryl group is substituted
  • alkylheteroaryl group wherein when heteroaryl group comprises only C and N in the ring, the aryl group is substituted by other than a methyl group
  • branched alkenyl (ix) alkyl-alcohol group or alkenyl-alcohol group (x) amide or alkylamide wherein (a) the alkyl of the alkylamide is -CH 2 - or - CH 2 CH 2 -, (b) the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • R 8 is an alkyloxyalkyl group.
  • the alkyloxyalkyl group is a -alkyl-O-alkyl group.
  • Each alkyl of the group is preferably independently has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • Each alkyl of the group may be independently branched or straight chain. Preferably one or each alkyl is straight chain
  • alkyloxyalkyl groups are -EtOEt, -EtOMe, -MeOEt, and -MeOMe.
  • R 8 may be a nitrile group or comprise a nitrile group.
  • Nitrile group is understood to mean a -C ⁇ N group.
  • R 8 is a nitrile group. In one preferred aspect when R 8 is a nitrile group, R 2 : is -OH.
  • R 8 is a nitrile group and R 2 is -OH.
  • R 2 is capable of forming a hydrogen bond.
  • the term "capable of forming a hydrogen bond” as used herein means a group having a region of negative charge capable of forming one part of a hydrogen bond.
  • R 8 is an alkylaryl group.
  • alkylaryl group it is meant a group denoted by -alkyl-aryl.
  • the alkyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • the alkyl group may be branched or straight chain. Preferably the alkyl group is straight chained.
  • the aryl group typically has a six membered ring
  • the aryl group is substituted.
  • the aryl group of the alkylaryl group is substituted by a group selected from N,N-dialkyl, alkoxy, nitro, nitrile, and azaalkyl groups.
  • N,N-dialkyl is -N(C1-10 alkyl) 2> -N(C1-5 alkyl) 2 , or -N(C1-3 alkyl) 2 .
  • NMe 2 is particularly preferred.
  • the alkoxy group is C1-10 alkoxy, C1-5 alkoxy, and C1-3 alkoxy. Particularly preferred is methoxy.
  • alkylaryl group is -CH 2 -Ph.
  • R 8 is an alkenylaryl group.
  • alkylaryl group it is meant a group denoted by -alkenyl-aryl.
  • the aryl group of the alkenylaryl group is substituted.
  • the alkenyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1, 2 or 3 carbons.
  • the alkenyl group may be branched or straight chain. Preferably the alkenyl group is straight chained.
  • the aryl group typically has a six membered ring
  • the aryl group is substituted.
  • the aryl group of the alkylaryl group is substituted by a group selected from N,N-dialkyl, alkoxy, nitro, nitrile, and azaalkyl groups.
  • N.N-dialkyl is -N(CMO alkyl) 2 , -N(C1-5 alkyl) 2 , or -N(C1-3 alkyl) 2 .
  • NMe 2 is particularly preferred.
  • the alkoxy group is C1-10 alkoxy, C1-5 alkoxy, and C1-3 alkoxy. Particularly preferred is methoxy.
  • R 8 is an alkylheteroaryl group.
  • the alkyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • the alkyl group may be branched or straight chain. Preferably the alkyl group is straight chained.
  • the aryl group typically has a six membered ring
  • the heteroarylgroup contain carbon and hetero atoms.
  • Typical hetero atoms include O, N and S, in particular N.
  • the aryl group may be substituted or unsubstituted.
  • the aryl group is substituted.
  • the aryl group of the alkylaryl group is substituted by a group selected from N,N-dialkyl, alkoxy, nitro, nitrile, and azaalkyl groups.
  • N,N-dialkyl is -N(C1-10 alkyl) 2 , -N(C1-5 alkyl) 2 , or -N(C1-3 alkyl) 2 .
  • NMe 2 is particularly preferred.
  • the alkoxy group is C1-10 alkoxy, C1-5 alkoxy, and C1-3 alkoxy. Particularly preferred is methoxy.
  • R 8 is an alkenylheteroaryl group. In one preferred aspect, R 8 is an alkenylheteroaryl group, wherein the aryl group is substituted. Preferably R 8 is an alkenylheteroaryl group wherein the aryl group is unsubstituted.
  • R 8 is an alkylheteroaryl group.
  • the alkenyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • the alkenyl group may be branched or straight chain. Preferably the alkenyl group is straight chained.
  • the aryl group typically has a six membered ring
  • the heteroarylgroup contain carbon and hetero atoms. Typical hetero atoms include O, N and S, in particular N.
  • the aryl group may be substituted or unsubstituted.
  • the aryl group is substituted.
  • the aryl group of the alkylaryl group is substituted by a group selected from N,N-dialkyl, alkoxy, nitro, nitrile, and azaalkyl groups.
  • N.N-dialkyl is -N(C1-10 alkyl) 2 , -N(C1-5 alkyl) 2 , or -N(C1-3 alkyl) 2 .
  • NMe 2 is particularly preferred.
  • the alkoxy group is C1-10 alkoxy, C1-5 alkoxy, and C1-3 alkoxy. Particularly preferred is methoxy.
  • alkenylheteroaryl group is selected from
  • the alkyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • the alkyl group may be branched or straight chain. Preferably the alkyl group is straight chained. Branched Alkenyl
  • R 8 is a branched alkenyl group.
  • the branched alkenyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2, 3 or 4 carbons.
  • Alkyl-Alcohol Group Or Alkenyl-Alcohol Group
  • R 8 is an alkyl-alcohol group or alkenyl- alcohol group.
  • R 8 is an alkyl-alcohol group.
  • the alkyl group may be branched or straight chain. Preferably the alkyl group is straight chained.
  • alkyl-alcohol group or alkenyl-alcohol group it is meant a group of the formula C ⁇ H 2x-2 n- y (OH)y wherein x is an integer, y is an integer and n is the degree of unsaturation.
  • x is from 1 to 20, preferably from 1 to 10, preferably from 1 to 5, preferably 1 , 2, 3 or 4.
  • y is 1 , 2 or 3.
  • n is 0, 1 , 2 or 3.
  • alkenyl-alcohol has the following structural formula:
  • the alkenyl alcohol is substituted.
  • a substituent replaces H 3 and/or H b in the following structural formula:
  • Suitable substituents include ester groups, haloalkyl groups, aryl groups such as heteroaryl groups, and alkyl groups.
  • Preferred substituted alkenyl-alcohol groups include
  • Ri 6 is a hydrocarbyl group, preferably a hydrocarbon, more preferably an alkyl group, preferably having from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2, or 3 carbons.
  • R 16 is an ethyl group.
  • R 8 is an amide or alkylamide group.
  • R 8 is an amide or alkylamide wherein (a) the alkyl of the alkylamide is - CH 2 - or -CH 2 CH 2 -, (b) the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • R 8 is an amide or alkylamide wherein (a) the alkyl of the alkylamide is -CH 2 - or -CH 2 CH 2 -, (b) the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • Preferred amide groups include NHCO-C ⁇ oalkyl, CONH Ci. 10 alkyl, NHCO(CH 2 )i-ioCH 3 , CONH(CH 2 ) 1-10 CH 3 , NHCO(CH 2 ) 3-7 CH 3 , CONH(CH 2 ) 3 - 7 CH 3 , NHCO(CH 2 ) 6 CH 3 , CONH(CH 2 ) 6 CH 3 .
  • the amide or alkylamide is an alkylamide.
  • Preferred alkylamide groups include Cvioalkyl-CONH-Ci. loalkyl, Ci -10 alkyl-CONH(CH 2 )i.ioCH 3 , C 1-10 alkyl- NHCO(CH 2 )S -7 CH 3 , C 1-10 alkyl-CONH(CH 2 ) 3-7 CH 3 , C 1-10 alkyl-NHCO(CH 2 ) 6 CH 3 , Ci.i O alkyl- CONH(CH 2 ) 6 CH 3 .
  • the substituents of the di-substituted amide together form a cyclic structure.
  • substituents of the di-substituted amide together form an aryl ring.
  • the substituents of the di-substituted amide together form a heterocyclic ring.
  • R 8 is -CHO, or together with another of R 3 , R 4 , R 5 , R 6 and R 7 the enol tautomer thereof
  • R 8 is -CHO.
  • R 8 is selected from
  • R 11 and R 12 are independently selected from H and hydrocarbyl.
  • At least on one of Rn and R 12 is_H.
  • both Ri 1 and R 12 are H.
  • At least on one of R 11 and R 12 is hydrocarbyl.
  • both R 11 and R 12 are hydrocarbyl.
  • hydrocarbyl is selected from optionally substituted alkyl group, optionally substituted haloalkyl group, aryl group, alkylaryl group, alkylarylakyl group, and an alkene group.
  • the hydrocarbyl group is an optionally substituted alkyl group.
  • the hydrocarbyl group is selected from C 1 -C 10 alkyl group, such as CrC 6 alkyl group, and C 1 -C 3 alkyl group.
  • Typical alkyl groups include C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 7 alkyl, and C 8 alkyl.
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 together with another of R 3 , R 4 , R 5 , R 6 and R 7 forms a ring containing -C( O)-;
  • ring may contain any suitable atoms.
  • ring A may contain C and optionally one or more hetero atoms. Typical hetero atoms include O, N and S, in particular N.
  • ring A contains C and optionally one or more N atoms.
  • ring A contains only C atoms i.e. it is carbocyclic.
  • the ring will contain from 4 to 10 members.
  • the ring will contain 5, 6 or 7 members.
  • the substituents may be selected from any suitable substituents. Suitable substituents may be selected from:
  • amide or alkylamide wherein (a) the alkyl of the alkylamide is -CH 2 - or -CH 2 CH 2 -, (b) the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group.
  • Each of the suitable substituents (i) to (xii) are preferably as defined herein in respect of R 8 .
  • the ester may be selected from - CO 2 R 21 , -CH 2 CO 2 R 2I , and -CH 2 CH 2 CO 2 R 21 , wherein R 21 is a hydrocarbyl group.
  • R 21 is a hydrocarbon group. More preferably R 2 i is an alkyl group such as an alkyl group preferably having from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • the alkyl group may be branched or straight chain. Preferably the alkyl group is straight chained.
  • the alkyl group may be branched or straight chain.
  • the alkyl group is straight chained.
  • the alkyl group preferably has from 1 to 20 carbons, preferably from 1 to 10 carbons, preferably from 1 to 5 carbons, preferably 1 , 2 or 3 carbons.
  • the alkyl may be a CH 2 or CH 2 CH 2 group.
  • one of R 3 , R 4 , R 5 , R 6 and R 7 together with another of R 3 , R 4 , R 5 , Re and R 7 forms the ring
  • the compound is of Formula IX
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, and heteroaryl groups.
  • At least one of R 3 , R 4 , R 5 , Re and R 7 is selected from alkylheterocycle groups
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from alkenylheterocycle groups
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from alkylheteroaryl groups. In one aspect of the present invention at least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from alkenylheteroaryl groups
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from heteroaryl groups.
  • alkylheterocycle group alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, and heteroaryl groups are preferably as defined herein in respect of R 8 .
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is -CN.
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from optionally substituted pyrazole.
  • the optional substituents may be selected from -OH, hydrocarbyl groups, -CN, nitro, and halogens.
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from optionally substituted thiazole.
  • the optional substituents may be selected from -OH, hydrocarbyl groups, -CN, nitro, and halogens. In one preferred aspect the optional substituents are selected from -(R 3 i)o-r
  • R 30 wherein each of R 24 , R 25 , R 26 , and R 27 is independently selected from H and hydrocarbyl, wherein each R 28 is independently selected from H and hydrocarbyl; and wherein each of R 29 , R 30 , R 32 are independently selected from alkyl groups.
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from optionally substituted oxazole.
  • the optional substituents may be selected from -OH, hydrocarbyl groups, -CN, nitro, and halogens.
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from optionally substituted isoxazole.
  • the optional substituents may be selected from -OH, hydrocarbyl groups, -CN, nitro, and halogens.
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from optionally substituted pyridine.
  • the optional substituents may be selected from -OH, hydrocarbyl groups, -CN, nitro, and halogens.
  • At least one of R 3 , R 4 , R 5 , R 6 and R 7 is selected from optionally substituted pyrimidine.
  • the optional substituents may be selected from -OH, hydrocarbyl groups, -CN, nitro, and halogens.
  • each of R 24 , R 25 , R 26 , and R 27 is independently selected from H and hydrocarbyl, wherein each R 28 is independently selected from H and hydrocarbyl; and wherein each of R 29 , R 30 , R 32 are independently selected from alkyl groups.
  • the optional substituents may be selected from -OH, hydrocarbyl groups, -CN, nitro, and halogens.
  • the hydrocarbyl group is selected from optionally substituted alkyl group, optionally substituted haloalkyl group, aryl group, alkylaryl group, alkylarylakyl group, and an alkene group.
  • the hydrocarbyl group is an optionally substituted alkyl group.
  • the hydrocarbyl group is selected from C 1 -C 1 0 alkyl group, such as C 1 -C 6 alkyl group, and C 1 -C 3 alkyl group.
  • Typical alkyl groups include C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl, C 7 alkyl, and C 8 alkyl.
  • the compound of the present invention may have substituents other than those of the ring systems show herein.
  • the ring systems herein are given as general formulae and should be interpreted as such.
  • the absence of any specifically shown substituents on a given ring member indicates that the ring member may substituted with any moiety of which H is only one example.
  • the ring system may contain one or more degrees of unsaturation, for example is some aspects one or more rings of the ring system is aromatic.
  • the ring system may be carbocyclic or may contain one or more hetero atoms.
  • the compound of the invention in particular the ring system compound of the invention of the present invention may contain substituents other than those show herein.
  • substituents may be one or more of: one or more sulphamate group(s), one or more phosphonate group(s), one or more thiophosphonate group(s), one or more sulphonate group(s), one or more sulphonamide group(s), one or more halo groups, one or more O groups, one or more hydroxy groups, one or more amino groups, one or more sulphur containing group(s), one or more hydrocarbyl group(s) - such as an oxyhydrocarbyl group.
  • the ring system of the present compounds may contain a variety of non- interfering substituents.
  • the ring system A'B'C'D' may contain one or more hydroxy, alkyl especially lower (CrC 6 ) alkyl, e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and other pentyl isomers, and n-hexyl and other hexyl isomers, alkoxy especially lower (C 1 -C 6 ) alkoxy, e.g. methoxy, ethoxy, propoxy etc., alkinyl, e.g. ethinyl, or halogen, e.g. fluoro substituents.
  • the ring system is substituted with a oxyhydrocarbyl group. More preferably the A' ring of the ring system is substituted with a oxyhydrocarbyl group.
  • hydrocarbylsulphanyl means a group that comprises at least hydrocarbyl group (as herein defined) and sulphur, preferably -S-hydrocarby I, more preferably -S-hydrocarbon. That sulphur group may be optionally oxidised.
  • the hydrocarbylsulphanyl group is -S-Ci -10 alkyl, more preferably -S-Ci -5 alkyl, more preferably -S-Ci -3 alkyl, more preferably -S-CH 2 CH 2 CH 3 , -S-CH 2 CH 3 or - SCH 3
  • the ring system is substituted with an alkyl group.
  • the alkyl group is ethyl.
  • the compound comprises at least two or more of sulphamate group, a phosphonate group, a thiophosphonate group, a sulphonate group or a sulphonamide group.
  • the compound comprises at least two sulphamate groups.
  • the compound comprises at least two sulphamate groups, wherein said sulphamate groups are not on the same ring.
  • the A' ring of the ring system comprises at least one sulphamate group and wherein the D' ring of the ring system comprises at least one sulphamate group.
  • the present invention provides a compound of Formula I compound of Formula I
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 1 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted wherein X is a bond or a linker group wherein
  • R 9 is selected from alkyl and halogen groups; and (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NR 1 R 2 ; wherein Ri and R 2 are independently selected from H and hydrocarbyl OR
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group, (xi) -CHO, or together with another of R 3 , R 4 , R 5 , Re and R 7 the enol tautomer thereof OR
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted wherein X is a bond or a linker group wherein
  • R 9 is selected from alkyl and halogen groups; and (ii) R 10 is selected from -OH, oxyhydrocarbyl and -OSO 2 NR 1 R 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl OR
  • alkenylaryl group wherein the aryl group is substituted
  • alkylheteroaryl group wherein when heteroaryl group comprises only C and N in the ring, the aryl group is substituted by other than a methyl group
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • a pharmaceutical composition comprising a compound of Formula I Formula I wherein R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 , are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted wherein X is a bond or a linker group wherein
  • R 9 is selected from alkyl and halogen groups; and (ii) Ri 0 is selected from -OH, oxyhydrocarbyl and -OSO 2 NRiR 2 ; wherein R-i and R 2 are independently selected from H and hydrocarbyl OR
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group, (xi) -CHO, or together with another of R 3 , R 4 , R 5 , R 6 and R 7 the enol tautomer thereof OR
  • the present invention provides use of a compound in the manufacture of a medicament for use in the therapy of a condition or disease associated with 17 ⁇ - hydroxysteroid dehydrogenase (17 ⁇ -HSD), wherein the compound is of Formula I
  • R 3 , R 4 , R 5 , R 6 , R 7 , Rg, and R 1 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted wherein X is a bond or a linker group wherein
  • Rg is selected from alkyl and halogen groups; and (ii) R 1 0 is selected from -OH, oxyhydrocarbyl and -OSO 2 NRiR 2 ; wherein R 1 and R 2 are independently selected from H and hydrocarbyl OR
  • R 8 is a selected from (i) an alkyloxyalkyl group (ii) a nitrile group, and wherein R 2 is capable of forming a hydrogen bond (iii) alkylaryl group, wherein the aryl group is substituted by other than a C1-10 group
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group, (xi) -CHO, or together with another of R 3 , R 4 , R 5 , Re and R 7 the enol tautomer thereof OR
  • R 3 , R 4 , R 5 , R 6 , R 7 , R 9 , and R 10 are independently selected from -H, -OH, hydrocarbyl groups, oxyhydrocarbyl groups, cyano (-CN), nitro (-NO 2 ), and halogens; wherein ring A is optionally further substituted wherein X is a bond or a linker group wherein (A) (i) R 9 is selected from alkyl and halogen groups; and (ii) Rio is selected from -OH, oxyhydrocarbyl and -OSO 2 NRi R 2 ; wherein Ri and R 2 are independently selected from H and hydrocarbyl OR
  • the amide is di-substituted and/or (c) the amide is substituted with at least one of alkylheterocycle group, alkenylheterocycle group, alkylheteroaryl group, alkenylheteroaryl group, heteroaryl group, alkylamine group, alkyloxyalkyl group, alkylaryl group, straight or branched alkyl group,
  • a method comprising (a) performing a steroid dehydrogenase assay with one or more candidate compounds having the formula as defined herein; (b) determining whether one or more of said candidate compounds is/are capable of modulating steroid dehydrogenase activity; and (c) selecting one or more of said candidate compounds that is/are capable of modulating steroid dehydrogenase activity.
  • a method comprising (a) performing a steroid dehydrogenase assay with one or more candidate compounds having the formula as defined herein; (b) determining whether one or more of said candidate compounds is/are capable of inhibiting steroid dehydrogenase activity; and (c) selecting one or more of said candidate compounds that is/are capable of inhibiting steroid dehydrogenase activity.
  • the method may also include the step of modifying the identified candidate compound (such as by chemical and/or enzymatic techniques) and the optional additional step of testing that modified compound for steroid dehydrogenase inhibition effects (which may be to see if the effect is greater or different).
  • the method may also include the step of determining the structure (such as by use of crystallographic techniques) of the identified candidate compound and then performing computer modelling studies - such as to further increase its steroid dehydrogenase inhibitory action.
  • the present invention also encompasses a computer having a dataset (such as the crystallographic co-ordinates) for said identified candidate compound.
  • the present invention also encompasses that identified candidate compound when presented on a computer screen for the analysis thereof - such as protein binding studies.
  • the compounds have no, or a minimal, oestrogenic effect.
  • the compounds have an oestrogenic effect.
  • the compounds have a reversible action.
  • the compounds have an irreversible action.
  • the compounds of the present invention are useful for the treatment of breast cancer.
  • the compounds of the present invention may be in the form of a salt.
  • the compound of the present invention or for use in the present invention is selected from the following compounds:
  • the present invention also covers novel intermediates that are useful to prepare the compounds of the present invention.
  • the present invention covers novel alcohol precursors for the compounds.
  • the present invention covers bis protected precursors for the compounds. Examples of each of these precursors are presented herein.
  • the present invention also encompasses a process comprising each or both of those precursors for the synthesis of the compounds of the present invention.
  • present compounds may also inhibit the activity of steroid dehydrogenase (HSD).
  • HSD steroid dehydrogenase
  • steroid dehydrogenase or HSD it is meant 17 ⁇ hydroxy steroid dehydrogenase.
  • the 17 ⁇ hydroxy steroid dehydrogenase is EC 1.1.1.62
  • the HSD is of Type 3, 5 and/or 7.
  • the HSD converts androstenedione to testosterone.
  • the HSD is of Type 1 , 3, 5 and/or 7.
  • the HSD converts oestrone to oestradiol.
  • the HSD is of Type 2 and/or 8.
  • the HSD converts oestradiol to oestrone.
  • the steroid dehydrogenase is steroid dehydrogenase Type I. In some aspects of the present invention, it is preferred that the steroid dehydrogenase is steroid dehydrogenase Type Il
  • the HSD is of Type 1 , 3, 5 and/or 7.
  • the HSD converts oestrone to oestradiol .
  • the HSD is of Type 2 and/or 8.
  • the HSD converts oestradiol to oestrone.
  • Steroid dehydrogenase or "DH" for short may be classified as consisting of two types - Type I and Type II.
  • the two types of enzyme such as oestradiol 17 ⁇ -hydroxysteroid dehydrogenases (E2HSD), have pivotal roles in regulating the availability of ligands to interact with the oestrogen receptor.
  • Type I reduces oestrone (E1) to the biologically active oestrogen, oestradiol (E2) while E2HSD Type Il inactivates E2 by catalysing its oxidation to E1.
  • inhibitor includes reduce and/or eliminate and/or mask and/or prevent the detrimental action of DH.
  • the compound of the present invention is capable of acting as an DH inhibitor.
  • inhibitor as used herein with respect to the compound of the present invention means a compound that can inhibit DH activity - such as reduce and/or eliminate and/or mask and/or prevent the detrimental action of DH.
  • the DH inhibitor may act as an antagonist.
  • the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit DH activity.
  • the compounds defined herein may also inhibit steroid sulphatase.
  • Steroid sulphatase which is sometimes referred to as steroid sulphatase or steryl sulphatase or "STS" for short - hydrolyses several sulphated steroids, such as oestrone sulphate, dehydroepiandrosterone sulphate and cholesterol sulphate.
  • STS has been allocated the enzyme number EC 3.1.6.2.
  • STS is an enzyme that has been implicated in a number of disease conditions.
  • STS activity may also bring about disease conditions.
  • STS has also been implicated in other disease conditions.
  • Le Roy et al (Behav Genet 1999 Mar;29(2):131-6) have determined that there may be a genetic correlation between steroid sulphatase concentration and initiation of attack behaviour in mice. The authors conclude that sulphatation of steroids may be the prime mover of a complex network, including genes shown to be implicated in aggression by mutagenesis.
  • inhibit includes reduce and/or eliminate and/or mask and/or prevent the detrimental action of STS.
  • the compound of the present invention is capable of acting as an STS inhibitor.
  • inhibitor as used herein with respect to the compound of the present invention means a compound that can inhibit STS activity - such as reduce and/or eliminate and/or mask and/or prevent the detrimental action of STS.
  • the STS inhibitor may act as an antagonist.
  • the compound is further characterised by the feature that if the sulphamate group were to be substituted by a sulphate group to form a sulphate derivative, then the sulphate derivative would be hydrolysable by an enzyme having steroid sulphatase (E. C. 3.1.6.2) activity - i.e. when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37°C.
  • E. C. 3.1.6.2 an enzyme having steroid sulphatase
  • sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sulphatase (E. C. 3.1.6.2) activity and would yield a Km value of less than 200 mmolar, preferably less than 150 mmolar, preferably less than 100 mmolar, preferably less than 75 mmolar, preferably less than 50 mmolar, when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37°C.
  • E. C. 3.1.6.2 an enzyme having steroid sulphatase
  • sulphamate group of the compound were to be replaced with a sulphate group to form a sulphate compound then that sulphate compound would be hydrolysable by an enzyme having steroid sulphatase (E. C.
  • 150 ⁇ molar preferably less than 100 ⁇ molar, preferably less than 75 ⁇ molar, preferably less than 50 ⁇ molar, when incubated with steroid sulphatase EC 3.1.6.2 at pH 7.4 and 37°C.
  • the compound of the present invention is not hydrolysable by an enzyme having steroid sulphatase (E. C. 3.1.6.2) activity.
  • the compound of the present invention has at least about a 100 fold selectivity to a desired target (e.g. STS), preferably at least about a 150 fold selectivity to the desired target, preferably at least about a 200 fold selectivity to the desired target, preferably at least about a 250 fold selectivity to the desired target, preferably at least about a 300 fold selectivity to the desired target, preferably at least about a 350 fold selectivity to the desired target.
  • a desired target e.g. STS
  • a desired target e.g. STS
  • the compound of the present invention may have other beneficial properties in addition to or in the alternative to its ability to inhibit HSD activity.
  • the ring X has a sulphamate group as a substituent.
  • sulphamate as used herein includes an ester of sulphamic acid, or an ester of an N- substituted derivative of sulphamic acid, or a salt thereof.
  • R 10 is a sulphamate group then the compound of the present invention is referred to as a sulphamate compound.
  • the sulphamate group has the formula:
  • R 1 and R 2 are independently selected from H, alkyl, cycloalkyl, alkenyl and aryl, or combinations thereof, or together represent alkylene, wherein the or each alkyl or cycloalkyl or alkenyl or optionally contain one or more hetero atoms or groups.
  • the N-substituted compounds of this invention may contain one or two N-alkyl, N-alkenyl, N-cycloalkyl or N-aryl substituents, preferably containing or each containing a maximum of 10 carbon atoms.
  • R 1 and/or R 2 is alkyl
  • the preferred values are those where R 1 and R 2 are each independently selected from lower alkyl groups containing from 1 to 6 carbon atoms, that is to say methyl, ethyl, propyl etc.
  • R 1 and R 1 may both be methyl.
  • R 1 and/or R 2 is aryl
  • typical values are phenyl and tolyl (PhCH 3 ; o).
  • R 1 and R 2 represent cycloalkyl
  • typical values are cyclopropyl, cyclopentyl, cyclohexyl etc.
  • R 1 and R 2 typically represent an alkylene group providing a chain of 4 to 6 carbon atoms, optionally interrupted by one or more hetero atoms or groups, e.g. to provide a 5 membered heterocycle, e.g. morpholino, pyrrolidino or piperidino.
  • alkyl, cycloalkyl, alkenyl and aryl substituted groups are included containing as substituents therein one or more groups which do not interfere with the HSD inhibitory activity of the compound in question.
  • substituents include hydroxy, amino, halo, alkoxy, alkyl and aryl.
  • the sulphamate group may form a ring structure by being fused to (or associated with) one or more atoms in or on group X.
  • there may be two sulphamates i.e. bis-sulphamate compounds. If these compounds are based on a steroidal nucleus, preferably the second (or at least one of the additional) sulphamate group is located at position 17 of the steroidal nucleus. These groups need not be the same.
  • At least one of R 1 and R 2 is H.
  • each of R-i and R 2 is H.
  • Steroid sulphatase activity is measured in vitro using intact MCF-7 human breast cancer cells. This hormone dependent cell line is widely used to study the control of human breast cancer cell growth. It possesses significant steroid sulphatase activity (Maclndoe et al. Endocrinology, 123, 1281-1287 (1988); Purohit & Reed, Int. J. Cancer, 50, 901- 905 (1992)) and is available in the U.S.A. from the American Type Culture Collection (ATCC) and in the U.K. (e.g. from The Imperial Cancer Research Fund).
  • ATCC American Type Culture Collection
  • MEM Minimal Essential Medium
  • HEPES Flow Laboratories, Irvine, Scotland
  • 5% foetal bovine serum 20 mM HEPES
  • 2 mM glutamine nonessential amino acids
  • 0.075% sodium bicarbonate Up to 30 replicate 25 cm2 tissue culture flasks are seeded with approximately 1 x 10 5 cells/flask using the above medium. Cells are grown to 80% confluency and the medium is changed every third day.
  • Intact monolayers of MCF-7 cells in triplicate 25 cm 2 tissue culture flasks are washed with Earle's Balanced Salt Solution (EBSS from ICN Flow, High Wycombe, U.K.) and incubated for 3-4 hours at 37 0 C with 5 pmol (7 x 10 5 dpm) [6,7-3H]oestrone-3-sulphate (specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) in serum-free MEM (2.5 ml) together with oestrone-3-sulphamate (11 concentrations: 0; 1fM; 0.01 pM; 0.1pM; 1pM; 0.01 nM; 0.1nM; 1nM; O.OImM; CUmM; 1mM).
  • EBSS Earle's Balanced Salt Solution
  • the mass of oestrone-3-sulphate hydrolysed was calculated from the 3H counts obtained (corrected for the volumes of the medium and organic phase used, and for recovery of [14C] oestrone added) and the specific activity of the substrate.
  • Each batch of experiments includes incubations of microsomes prepared from a sulphatase-positive human placenta (positive control) and flasks without cells (to assess apparent non- enzymatic hydrolysis of the substrate). The number of cell nuclei per flask is determined using a Coulter Counter after treating the cell monolayers with Zaponin. One flask in each batch is used to assess cell membrane status and viability using the Trypan Blue exclusion method (Phillips, H.J. (1973) In: Tissue culture and applications, [eds: Kruse, D.F. & Patterson, M. K.]; pp. 406-408; Academic Press, New York).
  • Results for steroid sulphatase activity are expressed as the mean ⁇ 1 S. D. of the total product (oestrone + oestradiol) formed during the incubation period (20 hours) calculated for 106 cells and, for values showing statistical significance, as a percentage reduction (inhibition) over incubations containing no oestrone-3-sulphamate. Unpaired Student's t-test was used to test the statistical significance of results.
  • Sulphatase-positive human placenta from normal term pregnancies are thoroughly minced with scissors and washed once with cold phosphate buffer (pH 7.4, 50 mM) then re-suspended in cold phosphate buffer (5 ml/g tissue). Homogenisation is accomplished with an Ultra-Turrax homogeniser, using three 10 second bursts separated by 2 minute cooling periods in ice. Nuclei and cell debris are removed by centrifuging (4 0 C) at 200Og for 30 minutes and portions (2 ml) of the supernatant are stored at 2O 0 C. The protein concentration of the supernatants is determined by the method of Bradford (Anal. Biochem., 72, 248-254 (1976)).
  • Incubations (1 ml) are carried out using a protein concentration of 100 mg/ml, substrate concentration of 20 mM [6,7-3H]oestrone-3-sulphate (specific activity 60 Ci/mmol from New England Nuclear, Boston, Mass., U.S.A.) and an incubation time of 20 minutes at 37 0 C. If necessary eight concentrations of compounds are employed: 0 (i.e. control); 0.05mM; 0.1mM; 0.2mM; 0.4mM; 0.6mM; 0.8mM; 1.OmM.
  • the compounds of the present invention may be studied using an animal model, in particular in ovariectomised rats.
  • an animal model in particular in ovariectomised rats.
  • compounds which are oestrogenic stimulate uterine growth in this model compounds which are oestrogenic stimulate uterine growth.
  • the compound (10 mg/Kg/day for five days) was administered orally to rats with another group of animals receiving vehicle only (propylene glycol).
  • a further group received the compound EMATE subcutaneously in an amount of 10 ⁇ g/day for five days.
  • samples of liver tissue were obtained and steroid sulphatase activity assayed using 3H oestrone sulphate as the substrate as previously described (see ANIMAL ASSAY MODEL FOR DETERMINING OESTROGENIC ACTIVITY
  • the compounds of the present invention may be studied using an animal model, in particular in ovariectomised rats.
  • an animal model in particular in ovariectomised rats.
  • compounds which are oestrogenic stimulate uterine growth.
  • the compound (10 mg/Kg/day for five days) was administered orally to rats with another group of animals receiving vehicle only (propylene glycol).
  • a further group received the estrogenic compound EMATE subcutaneously in an amount of 10 ⁇ g/day for five days.
  • uteri were obtained and weighed with the results being expressed as uterine weight/whole body weight x 100.
  • the compounds of the present invention may be used as therapeutic agents - i.e. in therapy applications.
  • the term "therapy” includes curative effects, alleviation effects, and prophylactic effects.
  • the therapy may be on humans or animals, preferably female animals.
  • the present invention provides a pharmaceutical composition, which comprises a compound according to the present invention and optionally a pharmaceutically acceptable carrier, diluent or excipient (including combinations thereof).
  • the pharmaceutical compositions may be for human or animal usage in human and veterinary medicine and will typically comprise any one or more of a pharmaceutically acceptable diluent, carrier, or excipient. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R. Gennaro edit. 1985). The choice of pharmaceutical carrier, excipient or diluent can be selected with regard to the intended route of administration and standard pharmaceutical practice.
  • the pharmaceutical compositions may comprise as - or in addition to - the carrier, excipient or diluent any suitable binder(s), lubricant(s), suspending agent(s), coating agent(s), solubilising agent(s).
  • Preservatives may be provided in the pharmaceutical composition.
  • preservatives include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid.
  • Antioxidants and suspending agents may be also used.
  • the pharmaceutical composition of the present invention may be formulated to be delivered using a mini-pump or by a mucosal route, for example, as a nasal spray or aerosol for inhalation or ingestable solution, or parenterally in which the composition is formulated by an injectable form, for delivery, by, for example, an intravenous, intramuscular or subcutaneous route.
  • the formulation may be designed to be delivered by both routes.
  • the agent is to be delivered mucosally through the gastrointestinal mucosa, it should be able to remain stable during transit though the gastrointestinal tract; for example, it should be resistant to proteolytic degradation, stable at acid pH and resistant to the detergent effects of bile.
  • compositions can be administered by inhalation, in the form of a suppository or pessary, topically in the form of a lotion, solution, cream, ointment or dusting powder, by use of a skin patch, orally in the form of tablets containing excipients such as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents, or they can be injected parenterally, for example intravenously, intramuscularly or subcutaneously.
  • compositions may be best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood.
  • compositions may be administered in the form of tablets or lozenges which can be formulated in a conventional manner.
  • the compound of the present invention may be used in combination with one or more other active agents, such as one or more other pharmaceutically active agents.
  • the compounds of the present invention may be used in combination with other STS inhibitors and/or other inhibitors such as an aromatase inhibitor (such as for example, 4hydroxyandrostenedione (4-OHA)) and/or steroids - such as the naturally occurring sterneursteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and/or other structurally similar organic compounds.
  • an aromatase inhibitor such as for example, 4hydroxyandrostenedione (4-OHA)
  • steroids - such as the naturally occurring sterneurosteroids dehydroepiandrosterone sulfate (DHEAS) and pregnenolone sulfate (PS) and/or other structurally similar organic compounds.
  • DHEAS dehydroepiandrosterone sulfate
  • PS pregnenolone sulfate
  • STS inhibitors for use in the present invention include EMATE, and either or both of the
  • the compound of the present invention may be used in combination with a biological response modifier.
  • biological response modifier includes cytokines, immune modulators, growth factors, haematopoiesis regulating factors, colony stimulating factors, chemotactic, haemolytic and thrombolytic factors, cell surface receptors, ligands, leukocyte adhesion molecules, monoclonal antibodies, preventative and therapeutic vaccines, hormones, extracellular matrix components, fibronectin, etc.
  • the biological response modifier is a cytokine.
  • cytokines examples include: interleukins (IL) - such as IH 1 IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL- 9, IL-10, IL-11 , IL-12, IL-19; Tumour Necrosis Factor (TNF) - such as TNF- ⁇ ; Interferon alpha, beta and gamma; TGF- ⁇ .
  • TNF Tumour Necrosis Factor
  • the cytokine is tumour necrosis factor (TNF).
  • the TNF may be any type of TNF - such as TNF- ⁇ , TNF- ⁇ , including derivatives or mixtures thereof. More preferably the cytokine is TNF- ⁇ . Teachings on TNF may be found in the art - such as WO-A-98/08870 and WO-A-98/13348.
  • a physician will determine the actual dosage which will be most suitable for an individual subject and it will vary with the age, weight and response of the particular patient.
  • the dosages below are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited.
  • compositions of the present invention may be administered by direct injection.
  • the composition may be formulated for parenteral, mucosal, intramuscular, intravenous, subcutaneous, intraocular or transdermal administration.
  • the agent may be administered at a dose of from 0.01 to 30 mg/kg body weight, such as from 0.1 to 10 mg/kg, more preferably from 0.1 to 1 mg/kg body weight.
  • the agents of the present invention may be administered in accordance with a regimen of 1 to 4 times per day, preferably once or twice per day.
  • the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.
  • administered also includes delivery by techniques such as lipid mediated transfection, liposomes, immunoliposomes, lipofectin, cationic facial amphiphiles (CFAs) and combinations thereof.
  • routes for such delivery mechanisms include but are not limited to mucosal, nasal, oral, parenteral, gastrointestinal, topical, or sublingual routes.
  • administered includes but is not limited to delivery by a mucosal route, for example, as a nasal spray or aerosol for inhalation or as an ingestable solution; a parenteral route where delivery is by an injectable form, such as, for example, an intravenous, intramuscular or subcutaneous route.
  • a mucosal route for example, as a nasal spray or aerosol for inhalation or as an ingestable solution
  • parenteral route where delivery is by an injectable form, such as, for example, an intravenous, intramuscular or subcutaneous route.
  • the STS inhibitors of the present invention can be formulated in any suitable manner utilising conventional pharmaceutical formulating techniques and pharmaceutical carriers, adjuvants, excipients, diluents etc. and usually for parenteral administration.
  • Approximate effective dose rates may be in the range from 1 to 1000 mg/day, such as from 10 to 900 mg/day or even from 100 to 800 mg/day depending on the individual activities of the compounds in question and for a patient of average (70Kg) bodyweight. More usual dosage rates for the preferred and more active compounds will be in the range 200 to 800 mg/day, more preferably, 200 to 500 mg/day, most preferably from 200 to 250 mg/day. They may be given in single dose regimes, split dose regimes and/or in multiple dose regimes lasting over several days. For oral administration they may be formulated in tablets, capsules, solution or suspension containing from 100 to 500 mg of compound per unit dose.
  • the compounds will be formulated for parenteral administration in a suitable parenterally administrable carrier and providing single daily dosage rates in the range 200 to 800 mg, preferably 200 to 500, more preferably 200 to 250 mg.
  • Such effective daily doses will, however, vary depending on inherent activity of the active ingredient and on the bodyweight of the patient, such variations being within the skill and judgement of the physician.
  • the compounds of the present invention may be useful in the method of treatment of a cell cycling disorder.
  • Yeast cells can divide every 120 min., and the first divisions of fertilised eggs in the embryonic cells of sea urchins and insects take only 1530 min. because one large pre-existing cell is subdivided. However, most growing plant and animal cells take 10-20 hours to double in number, and some duplicate at a much slower rate. Many cells in adults, such as nerve cells and striated muscle cells, do not divide at all; others, like the fibroblasts that assist in healing wounds, grow on demand but are otherwise quiescent.
  • FACS fluorescence-activated cell sorter
  • the stages of mitosis and cytokinesis in an animal cell are as follows
  • cell cycling is an extremely important cell process. Deviations from normal cell cycling can result in a number of medical disorders. Increased and/or unrestricted cell cycling may result in cancer. Reduced cell cycling may result in degenerative conditions. Use of the compound of the present invention may provide a means to treat such disorders and conditions. Thus, the compound of the present invention may be suitable for use in the treatment of cell cycling disorders such as cancers, including hormone dependent and hormone independent cancers.
  • the compound of the present invention may be suitable for the treatment of cancers such as breast cancer, ovarian cancer, endometrial cancer, sarcomas, melanomas, prostate cancer, pancreatic cancer etc. and other solid tumours.
  • cancers such as breast cancer, ovarian cancer, endometrial cancer, sarcomas, melanomas, prostate cancer, pancreatic cancer etc. and other solid tumours.
  • cell cycling is inhibited and/or prevented and/or arrested, preferably wherein cell cycling is prevented and/or arrested.
  • cell cycling may be inhibited and/or prevented and/or arrested in the G 2 /M phase.
  • cell cycling may be irreversibly prevented and/or inhibited and/or arrested, preferably wherein cell cycling is irreversibly prevented and/or arrested.
  • irreversibly prevented and/or inhibited and/or arrested it is meant after application of a compound of the present invention, on removal of the compound the effects of the compound, namely prevention and/or inhibition and/or arrest of cell cycling, are still observable. More particularly by the term “irreversibly prevented and/or inhibited and/or arrested” it is meant that when assayed in accordance with the cell cycling assay protocol presented herein, cells treated with a compound of interest show less growth after Stage 2 of the protocol I than control cells. Details on this protocol are presented below.
  • the present invention provides compounds which: cause inhibition of growth of oestrogen receptor positive (ER+) and ER negative (ER-) breast cancer cells in vitro by preventing and/or inhibiting and/or arresting cell cycling; and/or cause regression of nitroso-methyl urea (NMU)-induced mammary tumours in intact animals (i.e. not ovariectomised), and/or prevent and/or inhibit and/or arrest cell cycling in cancer cells; and/or act in vivo by preventing and/or inhibiting and/or arresting cell cycling and/or act as a cell cycling agonist.
  • NMU nitroso-methyl urea
  • MCF-7 breast cancer cells are seeded into multi-well culture plates at a density of 105 cells/well. Cells were allowed to attach and grown until about 30% confluent when they are treated as follows:
  • Cells are grown for 6 days in growth medium containing the COI with changes of medium/COI every 3 days. At the end of this period cell numbers were counted using a Coulter cell counter.
  • Steroids were extracted from the aqueous medium with diethyl ether (4ml).
  • the ether phase was decanted into separate tubes after freezing the aqueous phase in solid carbon dioxide-methanol mixture.
  • the ether was evaporated to dryness under a stream of air at 40 0 C. The residue was dissolved in a small volume of diethyl ether and applied to TLC plates containing a fluorescent indicator.
  • E1 and E2 were separated by TLC using DCM-Ethyl acetate (4:1 v/v). The position of the product from each incubation flask was marked on the TLC plate after visualisation under UV light. The marked regions were cut out and placed in scintillation vials containing methanol (0.5ml) to elute the product. The amount of 3 H-product formed and 14 C-EI or 14 C-E2 recovered were calculated after scintillation spectrometry. The amount of product formed was corrected for procedural losses and for the number of cells in each flask.
  • the compounds of the present invention may be useful in the treatment of a cell cycling disorder.
  • a particular cell cycling disorder is cancer.
  • Cancer remains a major cause of mortality in most Western countries. Cancer therapies developed so far have included blocking the action or synthesis of hormones to inhibit the growth of hormone-dependent tumours. However, more aggressive chemotherapy is currently employed for the treatment of hormone-independent tumours.
  • oestrogens undergo a number of hydroxylation and conjugation reactions after their synthesis. Until recently it was thought that such reactions were part of a metabolic process that ultimately rendered oestrogens water soluble and enhanced their elimination from the body. It is now evident that some hydroxy metabolites (e.g. 2- hydroxy and 16alpha-hydroxy) and conjugates (e.g. oestrone sulphate, E1S) are important in determining some of the complex actions that oestrogens have in the body.
  • hydroxy metabolites e.g. 2- hydroxy and 16alpha-hydroxy
  • conjugates e.g. oestrone sulphate, E1S
  • 2- and 16-hydroxylated oestrogens in relation to conditions that alter the risk of breast cancer. There is now evidence that factors which increase 2-hydroxylase activity are associated with a reduced cancer risk, while those increasing 16alpha-hydroxylation may enhance the risk of breast cancer. Further interest in the biological role of oestrogen metabolites has been stimulated by the growing body of evidence that 2-methoxyoestradiol is an endogenous metabolite with anti-mitotic properties.
  • 2-MeOE2 is formed from 2-hydroxy oestradiol (2-OHE2) by catechol oestrogen methyl transferase, an enzyme that is widely distributed throughout the body.
  • 2-MeOE2 inhibits the growth of tumours arising from the subcutaneous injection of Meth A sarcoma, B16 melanoma or MDA-MB-435 oestrogen receptor negative (ER-) breast cancer cells. It also inhibits endothelial cell proliferation and migration, and in vitro angiogenesis. It was suggested that the ability of 2-MeOE2 to inhibit tumour growth in vivo may be due to its ability to inhibit tumour- induced angiogenesis rather than direct inhibition of the proliferation of tumour cells.
  • 2-MeOE2 exerts its potent anti-mitogenic and anti-angiogenic effects. There is evidence that at high concentrations it can inhibit microtubule polymerisation and act as a weak inhibitor of colchicine binding to tubulin. Recently, however, at concentrations that block mitosis, tubulin filaments in cells were not found to be depolymerised but to have an identical morphology to that seen after taxol treatment. It is possible, therefore, that like taxol, a drug that is used for breast and ovarian breast cancer therapy, 2-MeOE2 acts by stabilising microtubule dynamics.
  • 2-MeOE2 While the identification of 2-MeOE2 as a new therapy for cancer represents an important advance, the bioavailability of orally administered oestrogens is poor. Furthermore, they can undergo extensive metabolism during their first pass through the liver. As part of a research programme to develop a steroid sulphatase inhibitor for breast cancer therapy, oestrone-3-O-sulphamate (EMATE) was identified as a potent active site-directed inhibitor. Unexpectedly, EMATE proved to possess potent oestrogenic properties with its oral uterotrophic activity in rats being a 100-times higher than that of oestradiol.
  • EMATE oestrone-3-O-sulphamate
  • rbcs red blood cells
  • the compound of the present invention provides a means for the treatment of cancers and, especially, breast cancer.
  • the compound of the present invention may be useful in the blocking the growth of cancers including leukaemias and solid tumours such as breast, endometrium, prostate, ovary and pancreatic tumours.
  • the compounds of the present invention may be useful in the control of oestrogen levels in the body - in particular in females.
  • some of the compounds may be useful as providing a means of fertility control - such as an oral contraceptive tablet, pill, solution or lozenge.
  • the compound could be in the form of an implant or as a patch.
  • the compounds of the present invention may be useful in treating hormonal conditions associated with oestrogen.
  • the compound of the present invention may be useful in treating hormonal conditions in addition to those associated with oestrogen.
  • the compound of the present invention may also be capable of affecting hormonal activity and may also be capable of affecting an immune response.
  • STS inhibitors may be useful in the enhancing the memory function of patients suffering from illnesses such as amnesia, head injuries, Alzheimer's disease, epileptic dementia, presenile dementia, post traumatic dementia, senile dementia, vascular dementia and post-stroke dementia or individuals otherwise seeking memory enhancement.
  • inflammatory conditions such as conditions associated with any one or more of: autoimmunity, including for example, rheumatoid arthritis, type I and H diabetes, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, thyroiditis, vasculitis, ulcerative colitis and Crohn's disease, skin disorders e.g. psoriasis and contact dermatitis; graft versus host disease; eczema; asthma and organ rejection following transplantation.
  • autoimmunity including for example, rheumatoid arthritis, type I and H diabetes, systemic lupus erythematosus, multiple sclerosis, myasthenia gravis, thyroiditis, vasculitis, ulcerative colitis and Crohn's disease, skin disorders e.g. psoriasis and contact dermatitis; graft versus host disease; eczema; asthma and organ rejection following transplantation.
  • STS inhibitors may prevent the normal physiological effect of DHE ⁇ A or related steroids on immune and/or inflammatory responses.
  • the compounds of the present invention may be useful in the manufacture of a medicament for revealing an endogenous glucocorticoid-like effect.
  • the compound/composition of the present invention may have other important medical implications.
  • the compound or composition of the present invention may be useful in the treatment of the disorders listed in WO-A-99/52890 - viz:
  • the compound or composition of the present invention may be useful in the treatment of the disorders listed in WO-A-98/05635.
  • cancer inflammation or inflammatory disease
  • dermatological disorders fever, cardiovascular effects, haemorrhage, coagulation and acute phase response, cachexia, anorexia, acute infection, HIV infection, shock states, graft-versus-host reactions, autoimmune disease, reperfusion injury, meningitis, migraine and aspirin-dependent anti-thrombosis; tumour growth, invasion and spread, angiogenesis, metastases, malignant, ascites and malignant pleural effusion; cerebral ischaemia, ischaemic heart disease, osteoarthritis, rheumatoid arthritis, osteoporosis, asthma, multiple sclerosis, neurodegeneration, Alzheimer's disease, atherosclerosis, stroke, vasculitis, Crohn's disease and ulcerative colitis; periodontitis, gingivitis; psoriasis
  • the compound or composition of the present invention may be useful in the treatment of disorders listed in WO-A-98/07859.
  • cytokine and cell proliferation/differentiation activity e.g. for treating immune deficiency, including infection with human immune deficiency virus; regulation of lymphocyte growth; treating cancer and many autoimmune diseases, and to prevent transplant rejection or induce tumour immunity
  • regulation of haematopoiesis e.g. treatment of myeloid or lymphoid diseases
  • promoting growth of bone, cartilage, tendon, ligament and nerve tissue e.g.
  • follicle-stimulating hormone for healing wounds, treatment of burns, ulcers and periodontal disease and neurodegeneration; inhibition or activation of follicle-stimulating hormone (modulation of fertility); chemotactic/chemokinetic activity (e.g. for mobilising specific cell types to sites of injury or infection); haemostatic and thrombolytic activity (e.g. for treating haemophilia and stroke); antiinflammatory activity (for treating e.g. septic shock or Crohn's disease); as antimicrobials; modulators of e.g. metabolism or behaviour; as analgesics; treating specific deficiency disorders; in treatment of e.g. psoriasis, in human or veterinary medicine.
  • composition of the present invention may be useful in the treatment of disorders listed in WO-A-98/09985.
  • macrophage inhibitory and/or T cell inhibitory activity and thus, anti-inflammatory activity i.e.
  • inhibitory effects against a cellular and/or humoral immune response including a response not associated with inflammation; inhibit the ability of macrophages and T cells to adhere to extracellular matrix components and fibronectin, as well as up-regulated fas receptor expression in T cells; inhibit unwanted immune reaction and inflammation including arthritis, including rheumatoid arthritis, inflammation associated with hypersensitivity, allergic reactions, asthma, systemic lupus erythematosus, collagen diseases and other autoimmune diseases, inflammation associated with atherosclerosis, arteriosclerosis, atherosclerotic heart disease, reperfusion injury, cardiac arrest, myocardial infarction, vascular inflammatory disorders, respiratory distress syndrome or other cardiopulmonary diseases, inflammation associated with peptic ulcer, ulcerative colitis and other diseases of the gastrointestinal tract, hepatic fibrosis, liver cirrhosis or other hepatic diseases, thyroiditis or other glandular diseases, glomerulonephritis or other renal and urologic diseases, otitis or other oto-rhino-
  • retinitis or cystoid macular oedema retinitis or cystoid macular oedema, sympathetic ophthalmia, scleritis, retinitis pigmentosa, immune and inflammatory components of degenerative fondus disease, inflammatory components of ocular trauma, ocular inflammation caused by infection, proliferative vitreo-retinopathies, acute ischaemic optic neuropathy, excessive scarring, e.g.
  • monocyte or leukocyte proliferative diseases e.g. leukaemia
  • monocytes or lymphocytes for the prevention and/or treatment of graft rejection in cases of transplantation of natural or artificial cells, tissue and organs such as cornea, bone marrow, organs, lenses, pacemakers, natural or artificial skin tissue.
  • the sulphamate compounds of the present invention may be prepared by reacting an appropriate alcohol with a suitable chloride.
  • the sulphamate compounds of the present invention may be prepared by reacting an appropriate alcohol with a suitable sulfamoyl chloride, of the formula R 1 R 2 NSO 2 CI.
  • the alcohol is derivatised, as appropriate, prior to reaction with the sulfamoyl chloride.
  • functional groups in the alcohol may be protected in known manner and the protecting group or groups removed at the end of the reaction.
  • the sulphamate compounds are prepared according to the teachings of Page et al (1990 Tetrahedron 46; 2059-2068).
  • the phosphonate compounds may be prepared by suitably combining the teachings of Page et al (1990 Tetrahedron 46; 2059-2068) and PCT/GB92/01586.
  • the sulphonate compounds may be prepared by suitably adapting the teachings of Page et al (1990 Tetrahedron 46; 2059-2068) and PCT/GB92/01586.
  • the thiophosphonate compounds may be prepared by suitably adapting the teachings of Page et al (1990 Tetrahedron 46; 2059-2068) and PCT/GB91/00270.
  • the present invention provides compounds for use as steroid dehydrogenase inhibitors, and pharmaceutical compositions for the same.
  • [5-(3-Ethyl-4-methoxyphenyl)-l-oxo-indan-2-yl]-acetic acid 14 (0.050 g, 0.15 mmol) was suspended in anhydrous DCM (10 mL) under an inert atmosphere.
  • EDCI (0.087 g, 0.46 mmol) was added followed by DMAP (10 mg, cat. amount) and Et 3 N (0.050 mL) and the mixture stirred at r.t. for 20-30 minutes.
  • 2-Aminomethyl pyridine (0.031 mL, 0.30 mmol) was added and the resultant mixture stirred for 25 h. The reaction was quenched with sat.
  • the first fraction was found to to be: l-(3'-Ethyl-4-hydroxy ⁇ biphenyl-3-yl)-ethanone 95
  • 6-(4-Methoxy-phenyl)-3,4-dihydro-2H-naphthalen-l-one 101 To a mixture of trifluoro-methanesulphonic acid 5-oxo-5 5 6 5 7,8-tetrahydro-naphthalen-2-yl ester 100 (0.147 g, 0.5 mmol), 4-methoxyphenyl boronic acid (0.114 g, 0.75 mmol), K 2 CO 3 (0.172 g, 1.25 mmol) and Bu 4 NBr (0.161 g, 0.5 mmol) in EtOH (1.5 mL) and water (3.5 mL) was added Pd(OAc) 2 (catalytic) and the reaction was micro waved at 150°C for 10 min.
  • 6-(3-Ethyl-4-hydroxyphenyI)-3,4-dihydro-2H-naphthalen-l-one l06 Procedure as for 6-(4-hydroxy-phenyl)-3,4-dihydro-2H-naphthalen-l-one 102, using 30 mg of 6-(3-ethyl-4-methoxyphenyl)-3 5 4-dihydro-2H-naphthalen-l-one 105. Water was added and the organic layer separated.

Abstract

Cette invention concerne un composé représenté par la formule (I) dans laquelle: R3, R4, R5, R6, R7, R9, et R10 sont indépendamment sélectionnés parmi des groupes -H, -OH, hydrocarbyle, des groupes oxyhydrocarbyle, cyano (-CN), nitro (-NO2), et des halogènes; le noyau A est éventuellement substitué; X représente une liaison ou un groupe de liaison; (A) (i) R9 est sélectionné parmi des groupes alkyle et halogène et (ii) R10 est sélectionné parmi -OH, oxyhydrocarbyle et -OSO2NR1R2, R1 et R2 étant indépendamment sélectionnés parmi H et hydrocarbyle; ou (B) au moins un des éléments R3, R4, R5, R6 et R7 représente le groupe -C(=O)-CR11 R12-R8, R8 étant sélectionné parmi: (i) un groupe alkyloxyalkyle; (ii) un groupe nitrile; (iii) un groupe alkylaryle, le groupe aryle étant substitué par un groupe différent d'un groupe C1-10; (iv) un groupe alcénylaryle, le groupe aryle étant substitué; (v) un groupe alkylhétéroaryle, quand le groupe hétéroaryle comprend uniquement C et N dans le noyau, le groupe aryle étant substitué par un groupe différent d'un groupe méthyle; (vi) un groupe alcénylhétéroaryle; (vii) un groupe =N-O-alkyle ou =N-O-H; (viii) un alcényle ramifié; (ix) un groupe alcool d'alkyle ou un groupe alcool d'alcényle; (x) un amide ou un alkylamide, (a) l'alkyle de l'alkylamide représentant -CH2- ou -CH2CH2-, (b) l'amide étant disubstitué et/ou (c) l'amide étant substitué par un groupe alkylhétérocycle et/ou un groupe alcénylhétérocycle et/ou un groupe alkylhétéroaryle et/ou un groupe alcénylhétéroaryle et/ou un groupe hétéroaryle et/ou un groupe alkylamine et/ou un groupe alkyloxyalkyle et/ou un groupe alkylaryle et/ou un groupe alkyle linéaire ou ramifié; (xi) -CHO, ou conjointement avec un autre élément R3, R4, R5, R6 ou R7 le tautomère énol de celui-ci, R11 et R12 étant indépendamment sélectionnés parmi H et hydrocarbyle; ou (C) au moins un des éléments R3, R4, R5, R6 ou R7 conjointement avec un autre élément R3, R4, R5, R6 ou R7 forme un noyau contenant -C(=O)-; ou (D) au moins un des éléments R3, R4, R5, R6 ou R7 est sélectionné parmi un groupe alkylhétérocycle, un groupe alcénylhétérocycle, un groupe alkylhétéroaryle, un groupe alcénylhétéroaryle, et des groupes hétéroaryle; ou (E) au moins un des éléments R3, R4, R5, R6 ou R7 est sélectionné parmi -CN, un groupe -C(R13)=N-O-alkyle, un groupe -C(R14)=N-O-H, pyrazole éventuellement substitué, thiazole éventuellement substitué, oxazole éventuellement substitué, isoxazole éventuellement substitué, pyridine éventuellement substituée, et pyrimidine éventuellement substituée, ou conjointement avec un autre élément R3, R4, R5, R6 ou R7 forme un noyau contenant l'élément azote, R13 et R14 étant indépendamment sélectionnés parmi H et hydrocarbyle.
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